Monocytes/macrophages play a critical role in the pathogenesis of human immunodeficiency virus (HIV) infection, both as targets viral replication and as sources of multifunctional cytokines. Endothelins, potent vasoactive peptides, are among the panoply of cytokines produced and secreted by macrophages. We have previously reported that the HIV-1 envelope glycoprotein, gp120, stimulates the secretion of endothelin-1 (ET-1) from human macrophages in a concentration- dependent manner, that circulating monocytes in HIV-infected individuals express the ET-1 gene, while cells from healthy controls do not, and that cerebral macrophages in patients with HIV-encephalopathy are positive for ET-1. Thus, monocytic endothelins appear to be stimulated during HIV infection and their potent vasoactive properties could potentially mediate alterations in the cerebral perfusion pattern associated with AIDS dementia complex. This work was published in the Journal of Immunology (150:4601, 1993). We are currently investigating the effect of HIV infection on both constitutive and stimulated production of ET-1 by human macrophages. This includes analysis of potential differences between macrophage tropic HIV isolates that are neurotropic and non-neurotropic to determine their influence on entry of HIV infected cells into the brain and , thus, their potential role in AIDS dementia. Inasmuch as AIDS is a disease characterized by dysregulation of cytokine production, we are also investigating the role of various cytokines in the regulation of ET-1 gene expression. We have found that the cytokine, interferon-gamma is capable of inducing the expression of ET-1 in human monocytes/ macrophages in a manner dependent on the concentration of the cytokine. Expression of the ET-1 gene in response to IFN gamma treatment occurs late compared to expression in response to other inducers, such as PMA, suggesting that induction of another cellular protein may precede induction of ET-1. We are investigating potential differences in the mechanism of induction of this gene by IFN gamma, PMA, and bacterial LPS. These findings will then be used to determine the mechanism of induction mediated by the HIV envelope protein.